Stress has been shown to induce resumption of drug seeking in laboratory animals. The experimental model is reinstatement of operant behavior following extinction of previously acquired drug self-administration. Physical stress in the form of electric foot-shock has been consistently shown to lead to reinstatement of heroin and cocaine seeking in rats (Shaham and Stewart, 1995;Erb et al., 1996;Shaham, 1996). This stress-induced reinstatement is blocked by the alpha-2 adrenergic receptor agonist clonidine (Erb et al., 2000;Shaham et al., 2000;Highfield et al., 2001). The alpha-2 agonists may act upon some final common pathway of stress-induced relapse, relevant to multiple drugs of abuse. We tested the effect of clonidine on stress- and cue-induced craving in human cocaine users in a laboratory study and found that responsivity to stress scripts was significantly attenuated by clonidine 0.1 and 0.2 mg;responsivity to drug-cue scripts was significantly attenuated at the higher clonidine dose (0.2 mg) only. Thus, clonidine may reduce cocaine craving and some physiological reactivity in drug abusers experiencing stressful situations or situations that remind them of drug use. To test the clinical utility of this finding, we are conducting a clinical trial of clonidine for the prevention of relapse to illicit opioid use in individuals in buprenorphine maintenance. We are using handheld electronic devices as part of our outcome measurement, so we should be able to determine whether clonidine is differentiallty effective in preventing lapses associated with stress exposure versus cue exposure. We are also evaluating the role of stress in relapse in natural-history studies in which we collect quantitative real-time data on the stress experienced by drug misusers in their daily lives. We evaluated the occurrence of stress in relation to craving, mood, relapse-trigger exposure, and cocaine use in methadone-maintained cocaine- and heroin-abusing outpatients who provided ecological momentary assessment (EMA) data on handheld computers. Ratings of stress were compared to those of craving and mood and past-hour exposure to putative drug-use triggers in randomly prompted entries, and in the 5 hours prior to participant-initiated cocaine use reports. Stress had significant positive relationships with current ratings of craving for cocaine, heroin, and tobacco and with ratings of tiredness, boredom, and irritation, and had significant negative relationships with ratings of happiness and relaxation. Stress was significantly greater in entries in which participants also reported past-hour exposure to negative-mood triggers, most of the drug-exposure triggers, or any trigger involving thoughts about drugs (e.g., tempted out of the blue). The linear increase in stress during the five hours preceding individual episodes of cocaine use was not significant, though there was a trend for such an increase before the use episodes that participants attributed to stressful states when they occurred. The findings suggest a complex role of stress in addiction. Stress reported in real time in the natural environment showed strong cross-sectional momentary relationships with craving, mood, and exposure to drug-use trigger. However, the prospective association between stress ratings and cocaine-use episodes was, at best, weak. This combination of expected and unexpected findings illustrates the value of collecting real-time, in-the-field behavioral data that can be quantified and aggregated for analysis.